Summary of Work: These studies identify critical target genes and alterations in genes that may be important in chemical carcinogenesis. Genetic alterations in oncogenes (eg.-ras) and tumor suppressor genes (eg. - p53 and p16) from rodent tumors induced by certain carcinogens and from human cancers of individuals exposed to environmental agents are being characterized in order to understand mechanisms of chemical carcinogenesis. In one set of investigations B-catenin mutations are being identified in chemically induced mouse liver tumors. Methyleugenol, used as a flavoring in food products, caused a significant increase in mouse liver tumors; and B-catenin mutations, but not H-ras mutations were detected in more than half of the tumors examined. B-catenin mutations cause an accumulation of B-catenin, upregulation of Wnt-signalling, and resultant cell proliferation and blocked apoptosis. Expression of B-catenin and down stream genes in these tumors are now being studied. We are also continuing our study to identify mouse lung tumor susceptibility genes that may have relevant human homologs. p16-Ink4a, an important tumor suppressor gene in the Rb pathway, may be a lung tumor susceptibility gene in certain inbred mouse strains. We are studying methylation of the p16 promoter region and alterations in expression of p16 and Rb in mouse lung and liver tumors from different hybrid mice. As part of the environmental genome project we are also examining the human p16 gene for polymorphisms that may predispose to lung cancer. In another research project human bladder cancers associated with exposure to benzidine are being examined by CGH for gains or losses of genetic material.